Research: State of the Art Professor Derek Pheby.

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Research: State of the Art Professor Derek Pheby

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Where are we starting from? (1) What we know: ME is a syndrome (defined by its symptoms, not underlying pathology) Characterised by multi-system dysfunction Varies in severity and duration Acute or insidious onset Range of trigger factors, frequently viral Most common in women, particularly young adults (though occurs at all ages)

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Where are we starting from? (2) What we don’t know Underlying pathology – one disease or several? How to treat it

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Where are we starting from? (3) Common myths: It doesn’t exist! If it does exist, it’s a psychological condition NICE has had the last word on the subject Graded exercise and cognitive behaviour therapy are effective treatments

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Research Activity (1) Published scientific papers: US 50% UK 30% Rest of world 20% - but it doesn’t really amount to a coherent corpus of scientific knowledge

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Research Activity (2) Why has all this work not advanced knowledge further? Vicissitudes of funding No coherent strategy No supportive infrastructure

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The Observatory project (1) Funded for three years by the Big Lottery Fund Sponsored by Action for ME Academic collaboration of three universities: London School of Hygiene and Tropical Medicine University of Hull University of East Anglia

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The Observatory project (2) Purpose: Fill gaps in knowledge Epidemiology Qualitative social research Create range of infrastructure facilities to support research

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The Biobank Aims : To develop a key resource for biomedical research, especially the investigation of biomarkers for diagnosis and prognosis.

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The Biobank (2) Specific main objectives: to establish a biobank for the study of ME/CFS, as a resource for high quality and ethically approved biomedical research studies benefiting from well catalogued blood samples, which are linkable to clinical and risk factors data; to investigate risk factors for severity; to correlate clinical phenotype with disease severity.

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The Biobank (3) Subsequently: to disseminate the resource to the research community to plan high throughput studies, benefiting from sample collections and rapid advancing sequencing (e.g. whole genome sequencing,) and other molecular techniques, such as those investigating immune and genetic biomarkers to link the Biobank to the planned ‘post- mortem’ tissue bank for the study of ME/CFS.

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The Biobank (4) Outcomes full implementation of the ME/CFS Biobank, including: recruitment of well characterised cases with ME/CFS and controls, blood sample collections and storage.

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The Biobank (5) Other Research Possibilities Linkage of data from stored biological samples with longitudinal clinical data from the Disease Register will enable identification of clinical and pathological factors associated with particular adverse outcomes of interest. e.g. what clinical and pathological factors may be associated with disease severity? This will contribute to the development of prevention strategies

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The Biobank (6) $1.5 million awarded by National Institutes of Health, Washington DC Making possible a very large increase in the scale of the project

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Post Mortem Tissue Archive – Pros & Cons Rationale To create an opportunity to study neurological and other tissues from people with ME, in order to investigate underlying disease processes. Post mortem tissue archives have been established and function effectively in other neurodegenerative diseases, and one for ME exists in the US

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MRC (3) – Aims (continued) Enhance understanding through study of cross-disease symptomology Address lack of capacity in CFS/ME research, and need for multidisciplinary teams Involve partnerships between CFS/ME researchers and leading investigators in other fields.

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MRC (4) - The Five Funded Projects Identifying the biological fingerprints of fatigue Dr Wan Ng, Newcastle University Understanding the pathogenesis of autonomic dysfunction in chronic fatigue syndrome and its relationship with cognitive impairment Professor Julia Newton, Newcastle University Modulation of aberrant mitochondrial function and cytokine production in skeletal muscle of patients with CFS by supplementary polyphenols Professor Anne McArdle, Universities of Liverpool & Leeds Can enhancing slow wave sleep SWS improve daytime function in patients with CFS? Professor David Nutt, Imperial College London Persistent fatigue induced by interferon-alpha: a new immunological model for chronic fatigue syndrome Dr Carmine Pariante, King’s College London

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MRC (5) - Identifying the biological fingerprints of fatigue Aims: To improve understanding of the mechanisms of fatigue by: analysing the immune systems of > 500 patients with primary Sjögren syndrome identifying immune system abnormalities in these patients in order to help identify the “biological fingerprints” of fatigue, hopefully leading to: new treatments. a clinical diagnostic test for CFS/ME.

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MRC (6) - Understanding the pathogenesis of autonomic dysfunction in CFS and its relationship with cognitive impairment Aims: To explore the causes of autonomic nervous system dysfunction (→ dizziness and light- headedness in 90% of PWME), using fMRI to measure changes in brain blood flow to the brain relating this to cognition and nervous system dysfunction, in order to lay the foundations for: new diagnostic tools better understanding of nervous system abnormalities development of targeted treatments

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MRC (7) Modulation of aberrant mitochondrial function and cytokine production in skeletal muscle of patients with CFS by supplementary polyphenols Aim: To use a newly-developed technique to study muscle mitochondria, in order to: learn more about how CFS/ME develops and becomes chronic

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MRC (8) - Can enhancing slow wave sleep improve daytime function in patients with CFS? Aims: To study sleep disturbance in CFS/ME. To measure the effect of drug-induced deep restorative sleep in CFS/ME patients on brain function while awake. To increase understanding of the impact of sleep disturbance CFS/ME sufferers, in order to develop new treatments.

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EUROMENE 30+ participating centres in 15 countries; Just submitted proposal to EU for €6 million to support collaborative research as part of the Horizon 2020 programme; Title: “Understanding ME/CFS: elucidating determinants, risk factors and pathways, in order to develop personalised preventive, diagnostic and therapeutic strategies”

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EUROMENE (2): Aims of the proposed project Increasing understanding of ME/CFS by:- mapping knowledge in a systems medicine model, enriched with novel nanoanalytical, new generation sequencing, proteome analysis data, and PET studies; developing an integrated translational platform incorporating new and existing knowledge, and well characterised patient cohorts in seven EU countries; leading to new diagnostic and therapeutic products, and optimal prevention and treatment strategies.

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Rituximab (1) A monoclonal antibody against the protein CD20, found on the surface of B lymphocytes. Function Rituximab destroys normal and malignant B cells that have CD20 on their surfaces.

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PACE: Definitely not the last word (2) Other weaknesses: Intention to treat analysis poorly applied Exaggerated claims regarding outcomes Improvements marginal for all therapies Many showed no improvement However, adverse consequences were rare.